System and method for producing particles and patterned films

ABSTRACT

A system including a mold having a fluoropolymer wherein the mold defines a plurality of cavities having a predetermined shape and a cross-sectional dimension less than about 100 micrometers; a roller; a surface in cooperation with the roller to form a nip point configured to receive the mold, wherein the nip point is further configured to receive a substantially liquid composition and accelerate entry of the substantially liquid composition into the cavity. A method of forming particles including applying a substantially liquid composition to a mold, wherein the mold comprises a fluoropolymer and defines a plurality of cavities each having a broadest cross-sectional dimension of less than about 100 micrometers; nipping the mold between a roller and a surface such that the substantially liquid composition enters the cavities of the mold; and hardening the substantially liquid composition in the cavities of the mold to form a particle within each cavity, wherein the particle has a size and shape that substantially mimics the size and shape of the cavity of the mold.

RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent Application60/979,710, filed Oct. 12, 2007, which is herein incorporated byreference in its entirety.

BACKGROUND

Nanotechnology is a fast growing industry with many potentialimplications on products ranging from lenses configured to manipulatelight to pharmaceuticals and drug delivery devices. Nanostructuredlenses can include lenses designed with nanometer scale structuresordered and arranged to polarize or focus light. In other applications,nanometer sized particles can be fabricated of engineered polymercompositions designed to package and deliver pharmaceutical or biologicmaterial to desired tissues or organs within a patient.

Nanotechnology based products, however, face unique hurdles inmanufacturing because the products include structures or components thathave a size or shape on the nanometer scale. In other words, althoughnanotechnology is a rapidly growing industry with many potentialapplications, the ability to fabricate nanometer scale products involume needs advancement.

Currently, products of or having nanometer size structures arefabricated in batch type processing. Many of these batch processesrequire high precision machinery with the capability of maintaining verylevel surfaces, typically relying on glass substrate components. Incertain instances, these processes can fabricate effective components;however, the processes typically fail to produce the yield that isrequired for mass production. Therefore, a need exists to transform thefabrication of nanometer scale products and components from batch typeprocesses to robust and dynamic roll to roll processing.

BRIEF DESCRIPTION OF THE DRAWINGS

Reference is made to the accompanying drawings which show illustrativeembodiments of the present invention and which should be read inconnection with the description of the invention.

FIG. 1 shows a configuration of two rollers forming a nip point.

FIG. 2 shows a configuration of two rollers forming a nip point.

FIG. 3 shows a configuration of a roller and a surface of a plateforming a nip point.

FIG. 4 shows a nip point configured to receive a mold.

FIG. 5 shows a system including more than one nip point.

FIG. 6 shows a diagram of a system of some embodiments of the presentinvention.

FIG. 7 shows a diagram of a system of some embodiments of the presentinvention.

FIG. 8 shows a diagram of a system of some embodiments of the presentinvention.

FIGS. 9A-9C show configurations with varying nip point contact areas.

FIG. 10 shows a configuration of a substrate and a mold nipped betweenthe surface of a roller and a surface of a plate.

FIG. 11 shows a configuration of a substrate and a mold nipped betweenthe surface of a roller and a surface of a plate.

FIG. 12 shows a configuration of a system with more than one nip point.

FIGS. 13A-13C show configurations for harvesting particles. FIG. 13Ashows a laminate treated with a soluble substance. FIG. 13B showsparticles adhered to a soluble substance on a laminate. FIG. 13C showsparticles contained within mold cavities and in contact with a solublesubstance.

FIG. 14 shows a configuration of a system in which a solvent is appliedto a laminate proximate the nip point.

FIG. 15 shows a configuration of a system in which a solvent is appliedto a laminate proximate the nip point.

FIG. 16 shows a configuration of a system in which a cover film and amold are combined at a nip point.

SUMMARY OF EMBODIMENTS OF THE INVENTION

According to some embodiments of the present invention, a method offorming nanoparticles comprises applying a substantially liquidcomposition to a mold, wherein the mold comprises a polymer and definesa plurality of cavities each having a broadest cross-sectional dimensionof less than about 100 micrometers; passing the mold through a nip pointsuch that the substantially liquid composition enters the cavities ofthe mold; and hardening the substantially liquid composition in thecavities of the mold to form a particle within each cavity, wherein theparticle has a size and shape that substantially mimics the size andshape of the cavity of the mold.

In some embodiments, passing the mold through a nip point furthercomprises nipping the substantially liquid composition between a coversheet and the mold. In some embodiments, a method of formingnanoparticles further comprises, before hardening, removing the coversheet from the mold wherein the cavities remain filled with thesubstantially liquid composition and land area of the mold between thecavities is substantially free from the liquid composition. In certainembodiments, the substantially liquid composition not contained in thecavities substantially remains in contact with the cover sheet uponremoval of the cover sheet from the mold.

In some embodiments, a method of forming nanoparticles includes, afterhardening, harvesting the particles from the mold. In certainembodiments, before hardening, the mold is nipped with a substrate tolaminate the substrate to the mold. In some embodiments, after nippingthe mold with the substrate, the method includes hardening thesubstantially liquid compositions and harvesting the particle from themold, wherein the harvesting includes separating the substrate from themold such that the substrate moves away from the mold with the particlesdisposed on the substrate. In some embodiments, the substrate is removedfrom the mold at a predetermined angle.

In some embodiments of the present invention, the polymer mold comprisesa fluoropolymer. In some embodiments, the polymer mold comprises afluoropolyether.

According to some embodiments, a method for harvesting particlesincludes passing a base substrate and an array of nanoparticles coupledtherewith through a nip point; applying a solvent proximate to the nippoint, wherein the solvent is capable of disengaging the particles fromthe base substrate and dispersed the particles into a solution; andcollecting the solution. In certain embodiments, the substrate includesa surface treated with a soluble substance. In some embodiments, thesolvent dissolves the soluble substance to release the particles intothe solution.

According to some embodiments of the present invention, a system formaking nanoparticles comprises a mold comprising a polymer, wherein themold defines a plurality of cavities and each cavity has a predeterminedshape and a cross-sectional dimension less than about 100 micrometers; adispenser for dispensing a deformable composition near the nip point oron a substrate; and a nip point configured to receive the mold andsubstrate with the deformable composition dispensed there between andnip the mold and substrate together and urge the deformable compositioninto the cavities of the mold. In some embodiments, a system furthercomprises a curing device operable to harden the deformable compositionin the cavities of the mold to form a particle that substantially mimicsthe shape and size of the cavity. In some embodiments, a system furthercomprises a second nip point configured to receive a base substratehaving the particles coupled therewith; and a solvent associated withthe second nip point wherein the solvent disassociates the particlesfrom contact with the base substrate.

According to some embodiments, a method of forming a structured filmincludes applying a deformable composition to a mold, wherein the moldcomprises a polymer and defines a plurality of cavities having across-sectional dimension of less than about 100 micrometers; laminatingthe mold with a first film in a nip point such that a portion of thedeformable composition enters the cavities of the mold and excessdeformable composition remains between the mold and the first film; andhardening the deformable composition, wherein the hardened compositionforms a patterned film having structures that substantially mimic thesize and shape of the cavities. In some embodiments, a method of forminga structured film further includes controlling thickness of the excessdeformable composition such that an overall thickness of the structuredfilm is obtained. In some embodiments, the polymer comprises aperfluoropolyether.

According to some embodiments of the present invention, a collection ofnanoparticles is made by a process comprising nipping a deformablecomposition between a cover sheet and a polymer mold, wherein the molddefines cavities having a cross-sectional dimension of less than about100 micrometers; separating the cover sheet from the mold after nippingthe deformable composition between the mold and cover sheet such thatthe cavities remain filled with the deformable composition and area onthe mold between the cavities is substantially free from deformablecomposition; hardening the deformable composition in the cavities suchthat nanoparticles are formed that substantially mimic size and shape ofthe cavities of the mold; and removing the nanoparticles from thecavities of the mold.

DETAILED DESCRIPTION OF EMBODIMENTS OF THE INVENTION

According to some embodiments, the present invention includes methodsand systems for forming micro and/or nanosized particles and/orpatterned films and/or harvesting the particles. In some embodiments, asystem of the present invention includes a mold comprising afluoropolymer and/or having a surface energy less than about 18 mN/m.The mold may define a surface having a plurality of cavities, eachcavity having a predetermined shape and a cross-sectional dimension lessof than about 100 micrometers. In some embodiments, the system includesa roller and a surface in cooperation with the roller to form a nippoint. The nip point may be configured to receive the mold or the moldand a backing or film layer. In some embodiments, the nip point isconfigured to accelerate the filling of the cavities. In someembodiments the nip point is configured to hold a bead of substantiallyliquid composition and accelerate entry of the substantially liquidcomposition into the cavities.

In some embodiments, a system of the present invention produces microand/or nanosized particles. In some embodiments, a method of formingparticles includes applying a substantially liquid composition to a moldand progressing the mold through a nip point in a continuous or batchprocess. In some embodiments, the mold may include a fluoropolymer andmay define a plurality of cavities having a broadest cross-sectionaldimension of less than about 100 micrometers. In some embodiments, themold is nipped between a roller and a surface such that thesubstantially liquid composition enters the cavities of the mold. Thesubstantially liquid composition may be hardened in the cavities of themold to form a particle within each cavity. In some embodiments, theparticle has a size and shape that substantially mimics the size andshape of the cavity of the mold.

In some embodiments a system of the present invention harvestsparticles. In some embodiments, a method for harvesting particlesincludes forming a covered mold with a film, where the film may have aside which is coated with a soluble substance which has an affinity ofthe particles. When the film is separated from the mold face (i.e., opencavity side), particles adhered to the coating are removed from the moldcavities. The coated film with the adhered particles may be fed betweena nip point holding a bead of solvent for the coating. The particlecovered cover film is presented to the nip with the particles andcoating face proximate to the solvent bead. In some embodiments thesolvent is capable of dissolving the soluble coating and therebyreleasing the particle into the solution of coating and solvent. In someembodiments the soluble coating is dissolved such that the particle isreleased from the film creating a dispersion of particle in a solutionof solvent and soluble coating. The dispersion of particles in solutionmay then be collected.

In some embodiments, a system of the present invention forms astructured film. A substantially liquid composition may be applied to amold and progressed through a nip point. In some embodiments, a firstfilm and the mold may be combined or laminated between a roller and asurface such that the substantially liquid composition enters thecavities of the mold. In some embodiments, the mold, liquid and firstfilm are treated such that the substantially liquid composition in thecavities of the mold hardens and adheres to the first film. In someembodiments, the mold is removed from the first film such that thehardened composition is removed from the mold and remains on the firstfilm thereby forming a patterned film having structures thatsubstantially mimic the size and shape of the cavities of the mold.

In some embodiments a first cover film and the mold may be combined at anip point such that the substantially liquid composition enters thecavities of the mold and is covered by the first cover film. In someembodiments, prior to entering the nip point, the substantially liquidcomposition can be applied to the mold, the first cover film, as a beadat the nip point, or combinations thereof. In some embodiments, thefirst cover film is removed such that the substantially liquidcomposition not in the cavities of the mold remains adhered to the firstcover film and not the mold surface. In these embodiments, the micro ornano cavities remain substantially filled by the substantially liquidcomposition. In some embodiments, the mold surface having the cavitiesor mold face may be combined with a second cover film and treated suchthat the substantially liquid composition in the cavities is hardenedand adheres to the second cover film. In some embodiments, when thesecond cover film is separated from the mold surface having cavitiesthereon, hardened composition from the cavities remain adhered to thesecond cover film and are removed from the cavities, thereby forming apatterned film having the hardened composition as structures thatsubstantially mimic the size and shape of the cavities of the mold.

In some embodiments a first cover film and the mold may be combined at anip point such that the substantially liquid composition enters thecavities of the mold and is covered by the first cover film. In someembodiments, prior to entering the nip point, the substantially liquidcomposition can be applied to the mold, the first cover film, as a beadat the nip point, or combinations thereof. In some embodiments, thefirst cover film is removed such that the substantially liquidcomposition not in the cavities of the mold remains adhered to the firstcover film and not the mold surface. In these embodiments, the micro ornano cavities remain substantially filled by the substantially liquidcomposition. In some embodiments, the liquid composition contained inthe cavities can be hardened or cured. After hardening, the hardenedcomposition can be removed to provide isolated discrete micro ornanoparticles having a size and shape that substantially mimic the sizeand shape of the cavities.

In some embodiments, as shown in FIG. 16, a first cover film 42 and mold38 may be combined at a nip point 14 such that the substantially liquidcomposition 40 enters the cavities 54 of mold 38 and is covered by thefirst cover film. In some embodiments, prior to entering the nip point14, the substantially liquid composition 40 can be applied to the mold,the first cover film, as a bead at the nip point, or combinationsthereof. In some embodiments, the first cover film is removed such thatthe substantially liquid composition 40 b not in the cavities of themold remains adhered to the first cover film 42 and not the mold surface54 a. In these embodiments, the micro or nano cavities 54 remainsubstantially filled with the substantially liquid composition 40 a. Thefirst cover film 42 is substantially looped around roller 10. In someembodiments, the loop of first cover film 42 is looped around guiderollers 10 a to prevent contact with roll 10 and to give a closed loopof first cover film 42 entering and exiting nip point 14.

Some embodiments of the present invention provide systems and methodsfor fabricating a patterned film of a single composition. According tosuch embodiments, a liquid composition is presented between a moldsurface having micro and/or nanosized cavities and a first cover filmand progressed through a nip point. In some embodiments, the liquidcomposition presented between the mold surface and first cover film isin excess of a quantity necessary to fill the cavities, as such bothfilling the cavities and creating a substantially continuous filmbetween the first cover film and the mold surface. In some embodiments,the cover film and the surface film are positioned and/or maintained ata fixed gap such that a substantially continuous film of liquidcomposition is achieved. Next, the liquid composition presented betweenthe mold and first cover film is treated, cured, hardened, or the like.The mold and first cover film can be separated from the hardened singlecomposition yielding a single composition patterned film. The patternedfilm can include a continuous or integral layer having surfacestructures on a surface that substantially mimic the size and shape ofthe cavities of the mold. According to some embodiments, the size,shape, spacing, orientation, or the like of the cavities of the mold canbe selected to yield a useful product. Such useful products can includea patterned film surface that manipulates light, by but not limited to,selected polarization, selected reflectance, selected focusing, selecteddistribution, combinations thereof, and the like.

Components of the System

Roller

In some embodiments, the system may include a roller or multiplerollers. In some embodiments, the rollers can be cylindrically shaped.In some embodiments, the roller is configured within the system torotate about a central axis. In some embodiments, the rotation of theroller is controlled by a motor. In some embodiments, the linearvelocity of the surface of the roller is equivalent to a roller speed ofabout 0 ft/min to about 25 ft/min. In some embodiments, the roller turnsat a speed of about 1 ft/min to about 24 ft/min. In some embodiments,the roller turns at a speed of about 2 ft/min to about 23 ft/min. Insome embodiments, the roller turns at a speed of about 3 ft/min to about22 ft/min. In some embodiments, the roller turns at a speed of about 4ft/min to about 21 ft/min. In some embodiments, the roller turns at aspeed of about 5 ft/min to about 20 ft/min. In some embodiments, theroller turns at a speed of about 6 ft/min to about 19 ft/min. In someembodiments, the roller turns at a speed of about 7 ft/min to about 18ft/min. In some embodiments, the roller turns at a speed of about 9ft/min to about 17 ft/min. In some embodiments, the roller turns at aspeed of about 10 ft/min to about 16 ft/min. In some embodiments, theroller turns at a speed of about 11 ft/min to about 15 ft/min. In someembodiments, the roller turns at a speed of about 12 ft/min to about 14ft/min. In some embodiments, the roller turns at a speed of about 13ft/min.

In some embodiments, the roller may include an elastic material and/or aplastic material. In one embodiment, the roller includes an elastichydrocarbon polymer, or a rubber material. In certain embodiments, anelastic roller may have a durometer hardness of about 20 A to about 100A. In other embodiments, an elastic roller may have a durometer hardnessof about 40 A to about 80 A. In some embodiments, roller hardness is inthe scale of OO (e.g., foam sponge), O (e.g., extra soft rubber), A(e.g., silicone rubber), D (e.g., plastics), combinations thereof or thelike.

In some embodiments, the roller may include an inelastic material. Insome embodiments, the roller may include steel, stainless steel,aluminum, titanium, copper, a precious metals coating, rubber, a rubbercoating, a polymer, combinations thereof or the like. In someembodiments, the rollers may have selected surface energies, highsurface energies, low surface energies, and surface energies to affect acontinuous coating or desired de-wetting.

The rollers can have a diameter selected according to the size of molds,particles, patterned films, or the like to be fabricated on or with thesystem or according to parameters such as speeds, tension, temperature,or the like to be used in the system. In other embodiments, the rollermay have a diameter of about 5 mm to about 60 mm. In some embodiments,the roller has a diameter of about 10 mm to about 40 mm. In otherembodiments, the roller has a diameter of about 20 mm to about 30 mm.

In some embodiments the roller may be heated or cooled. The roller maybe heated or cooled by any suitable method, such as electricity, fluid,convection or conduction.

In some embodiments, the system may include one or more rollers.

Plate

In some embodiments, the system includes a plate for receiving molds,masters, harvesting layers, or the like. In certain embodiments, theplate includes a substantially planar surface and can be movable oradjustable with three or more degrees of freedom.

In some embodiments, the plate is resistant to warping under pressure.In some embodiments, the plate is resistant to warping under hightemperatures. According to some embodiments, the plate conducts heat,includes a heater, includes a cooler, is passively or actively (by amotor) linearly actuated, is adjustable with respect to a roller,combinations thereof, or the like.

In some embodiments, the plate-includes aluminum. According to someembodiments, the plate includes stainless steel, coated with preciousmetals, titanium, ceramic, polymeric materials, glass and the like.

In certain embodiments, the plate is heated. The plate may be heated byany suitable method, including electricity, fluid, convection, orconduction. In some embodiments, the plate contains heating elements.The plate may also be heated by placing the plate on a separate heatingelement.

Nip Point

In some embodiments, the system includes at least one nip point.According to some embodiments, a nip point is formed between a surfacein cooperation with a roller. Referring to FIGS. 1 and 2, in someembodiments surface 11 is the surface of second roller 12, such that nippoint 14 is formed between roller 10 and second roller 12. Referring toFIG. 3, in other embodiments surface 11 is the surface of plate 16, suchthat nip point 18 is formed by roller 10 and plate 16. In alternativeembodiments one roller is reversibly driven with a motor, both rollersare reversibly driven by a single or independent motors, one or moreroller is freely rotatable and/or not driven, combinations thereof, orthe like.

According to some embodiments, roller 10 and surface 11 are positionedrelative to each other to form desired nip point, 14, 18. In someembodiments, the position of roller 10 may be adjusted relative to plate16. In some embodiments, the position of plate 16 may be adjustedrelative to roller 10. In some embodiments, roller 10 and a surface arepositioned to produce a desired pressure at nip point 14, 18. Theposition of roller 10 may be controlled by piston 20, 22. In someembodiments, pistons 20, 22 are air actuated pistons.

Referring to FIG. 4, in some embodiments, nip point 14, 18 is configuredto receive mold 38. In some embodiments, roller 10 and surface 11 arepositioned such that mold 38 may pass between them. Nip point 14, 18 mayalso be configured to receive substantially liquid composition 40. Incertain embodiments, the nip point 14, 18 is configured to acceleratethe filling of the cavities at the nip point 14, 18 and urge thesubstantially liquid composition into cavities or recessions 54 of mold38. In some embodiments, nip point 14, 18 is configured to receive anadditional material such as substrate 42.

In some embodiments, roller 10 and surface 11 are positioned such thatpressure is applied to mold 38 and/or the liquid composition and/or anyadditional materials at the nip point. In some embodiments, roller 10and surface 11 are controlled such that a predetermined amount ofpressure is applied to mold 38 and/or the liquid composition and/or anyadditional materials at the nip point. According to some embodiments,the pressure at the nip point is controlled by adjusting the position ofroller 10 and surface 11 relative to each other. In certain embodiments,the pressure is determined by the viscosity, hydrophilic/hydrophobicnature of the materials, surface tension of the liquid, surface energyof the rollers, surface energy of the films, surface energy of themolds, or the like. In some embodiments, about 0 psi to about 100 psi isapplied at nip point 14, 18. In some embodiments, about 5 psi to about95 psi is applied at nip point 14, 18. In certain embodiments, about 10psi to about 90 psi is applied at nip point 14, 18. In some embodiments,about 15 psi to about 85 psi is applied at nip point 14, 18. In someembodiments, about 20 psi to about 80 psi is applied at nip point 14,18. In some embodiments, about 25 psi to about 75 psi is applied at nippoint 14, 18. In some embodiments, about 30 psi to about 70 psi isapplied at nip point 14, IS. In some embodiments, about 35 psi to about65 psi is applied at nip point 14, 18. In some embodiments, about 40 psito about 60 psi is applied at nip point 14, 18. In some embodiments,about 45 psi to about 55 psi is applied at nip point 14, 18. In someembodiments, about 50 psi is applied at nip point 14, 18. According tosome embodiments, an amount of pressure is applied at the nip point toaccelerate entry of the substantially liquid composition 40 into mold38.

In some embodiments, plate 16 is configured to move linearly through anip point. In some embodiments, plate 16 includes grooves or tracks toguide movement of plate 16 through the nip point. In some embodiments,the movement of plate 16 is controlled by a motor. In some embodimentsthe roller and/or plate motor is controlled by an electronic controlunit that can be controlled by input of an end user or preprogrammed tocontrol the plate based on a set of parameters that include, but are notlimited to, viscosity of the materials to be molded, processing timesthat are based on the characteristics of the materials to be molded,starting materials, temperature, combinations thereof, and the like. Insome embodiments, plate 16 moves at a speed of about 0 to about 25ft/min. In some embodiments, plate 16 moves at a speed of about 1 toabout 15 ft/min. In other embodiments, plate 16 moves at a speed ofabout 3 to about 12 ft/min.

Referring to FIG. 5, according to some embodiments, a system includesmore than one nip point 14, 18. In some embodiments, first nip point 14is formed by roller 10 and a surface of second roller 12. In someembodiments, second roller 12 includes a substance which does not adhereto substantially liquid composition 40 described herein. In someembodiments, the substance includes PTFE and/or PE. In certainembodiments, second nip point 18 is formed by roller 10 and the surfaceof plate 16.

Referring to FIGS. 6 and 7, a system of some embodiments may include nippoint 14 formed by roller 10 and surface 11 of second roller 12. In someembodiments, roller 10 is larger in diameter than second roller 12. Inother embodiments, roller 10 is the same size as or is smaller indiameter than second roller 12. In certain embodiments, the position ofroller 10 is vertically adjustable. The position of roller 10 may becontrolled by piston 20. In some embodiments, second roller 12 may behorizontally adjustable. The position of second roller 12 may becontrolled by piston 22. Pistons 20, 22 may be attached to pressure line24. Second roller 12 may be adjusted horizontally to a desired positionrelative to roller 10, to form nip point 14 in a desired configurationand/or pressure. In some embodiments, a system may include plate 16.Second nip point 18 may be formed by roller 10 and a surface of plate16. In some embodiments, roller 10 may be adjusted vertically to adesired position relative to plate 16 to form second nip point 18. Incertain embodiments, plate 16 moves horizontally. Plate 16 may includetracks or grooves 26 to guide the horizontal, linear movement. In someembodiments, the length of plate 16 may move linearly through second nip18 point formed by the surface of plate 16 and roller 10. In someembodiments, at least one of roller 10, second roller 12, and/or plate16 are heated.

In some embodiments, roller 10, second roller 12, and/or plate 16 may beheated by any suitable method, including electricity, fluid, convection,or conduction. In some embodiments, the plate contains heating elements.In certain embodiments, the system includes electronic control unit 28.Unit 28 may control various parameters of the system, including pistons20, 22, pressure, speed, and temperature of the components of thesystem. Electronic control unit 28 may be connected with a userinterface. In some embodiments, electronic control unit 28 controls thesystem based upon settings selected specifically for the materials to beused and/or fabricated with the system. In some embodiments, the systemincludes a port for applying substantially liquid composition 40 to mold38. In some embodiments, the port may include a dropper. In someembodiments, an inkjet type system can be used to add the substantiallyliquid composition 40 to mold 38 in precise quantities. An inkjet typesystem may be used to fill molds with natural dewetting. In someembodiments, a pumping mechanism is used to add and remove solventand/or substantially liquid composition 40 to the system.

Referring to FIG. 8, a system of some embodiments may include curingdevice 30. In some embodiments, curing device 30 may include a heater,actinic radiation, a pressure applicator, moisture cure, combinationsthereof, and the like. In certain embodiments, the system may includethird nip point 32. According to some embodiments, third nip point 32may be formed by third roller 34 and a surface of plate 16. Third roller34 may be adjusted vertically to a desired position relative to plate 16to form third nip point 32. In some embodiments, third roller 34 ismoved vertically by vertical piston 36. In some embodiments, afterfilling the cavities at a first nip point, the mold and cover sheet orbacking layer which covers the side of the mold that has the cavitiesthereon/therein can be separated at a downstream nip point to de-wetexcess substance from the surface of the mold and leave the liquidcomposition only in the cavities. In some embodiments after filling thecavities at a first nip point, mold and backing layer can be separatedat a downstream nip to separate the particles from the mold and leavethe particles on the backing layer. In some embodiments, the surfaceenergy of the cover sheet can be selected based on the properties of theliquid composition to be molded, mold, cavity size, shape, combinationsthereof, and their interaction.

Mold

According to some embodiments, a system may include mold 38. Mold 38 mayinclude a plurality of cavities. In some embodiments, the mold cavitiesmay have a substantially predetermined size and shape. In oneembodiment, the largest dimension of the cavity is less than about 100microns. In another embodiment, the largest dimension of the cavity isless than about 90 microns. In another embodiment, the largest dimensionof the cavity is less than about 80 microns. In another embodiment, thelargest dimension of the cavity is less than about 70 microns. Inanother embodiment, the largest dimension of the cavity is less thanabout 60 microns. In another embodiment, the largest dimension of thecavity is less than about 50 microns. In another embodiment, the largestdimension of the cavity is less than about 40 microns. In anotherembodiment, the largest dimension of the cavity is less than about 30microns. In another embodiment, the largest dimension of the cavity isless than about 20 microns. In another embodiment, the largest dimensionof the cavity is less than about 10 microns. In another embodiment, thelargest dimension of the cavity is less than about 9 microns. In anotherembodiment, the largest dimension of the cavity is less than about 8microns. In another embodiment, the largest dimension of the cavity isless than about 7 microns. In another embodiment, the largest dimensionof the cavity is less than about 6 microns. In another embodiment, thelargest dimension of the cavity is less than about 5 microns. In anotherembodiment, the largest dimension of the cavity is less than about 4microns. In another embodiment, the largest dimension of the cavity isless than about 3 microns. In another embodiment, the largest dimensionof the cavity is less than about 2 microns. In another embodiment, thelargest dimension of the cavity is less than about 1 microns.

In another embodiment, the largest dimension of the cavity is less thanabout 950 nanometers. In another embodiment, the largest dimension ofthe cavity is less than about 900 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 850 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 800 nanometers. In another embodiment, the largest dimension ofthe cavity is less than about 750 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 700 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 650 nanometers. In another embodiment, the largest dimension ofthe cavity is less than about 600 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 550 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 500 nanometers. In another embodiment, the largest dimension ofthe cavity is less than about 450 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 400 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 350 nanometers. In another embodiment, the largest dimension ofthe cavity is less than about 300 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 250 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 200 nanometers. In another embodiment, the largest dimension ofthe cavity is less than about 150 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 100 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 50 nanometers. In another embodiment, the largest dimension of thecavity is less than about 45 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 40 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 35 nanometers. In another embodiment, the largest dimension of thecavity is less than about 30 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 25 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 20 nanometers. In another embodiment, the largest dimension of thecavity is less than about 15 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 10 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 9 nanometers. In another embodiment, the largest dimension of thecavity is less than about 8 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 7 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 6 nanometers. In another embodiment, the largest dimension of thecavity is less than about 5 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 4 nanometers. Inanother embodiment, the largest dimension of the cavity is less thanabout 3 nanometers. In another embodiment, the largest dimension of thecavity is less than about 2 nanometers. In another embodiment, thelargest dimension of the cavity is less than about 1 nanometer.

Materials that can be useful with and/or as the mold materials used inthe present invention include, in some embodiments, substantiallysolvent resistant, low surface energy polymeric materials. In otherembodiments, mold 38 can be or include a solvent resistantelastomer-based material, such as but not limited to a fluoropolymer, afluorinated elastomer-based material, a fluoropolyether,perfluoropolyether, combinations thereof, or the like. In otherembodiments, the mold can have a surface energy below about 25 mN/m. Infurther embodiments, the mold can have a surface energy below about 20mN/m. In still further embodiments, the mold can have a surface energybelow about 18 mN/m. In yet another embodiment of the present invention,the mold can have a surface energy below about 15 mN/m. In yet anotherembodiment, the mold can have a surface energy below about 12 mN/m. Inanother embodiment of the present invention, the mold can have a surfaceenergy below about 10 mN/n.

Representative substantially solvent resistant elastomer-based materialsinclude but are not limited to fluorinated elastomer-based materials. Asused herein, the term “substantially solvent resistant” refers to amaterial, such as an elastomeric material that neither swells nordissolves beyond a nominal amount in common hydrocarbon-based organicsolvents or acidic or basic aqueous solutions. Representativefluorinated elastomer-based materials include but are not limited tofluoropolyether and perfluoropolyether (collectively PFPE) basedmaterials.

The mold materials of the present invention further include photocurableand/or thermal curable components such that the PFPE materials can becured from a liquid to a solid upon application of a treatment such asactinic radiation or thermal energy. PFPE materials and modified PFPEmaterials that are applicable to making the molds of the presentinvention are described herein and it will be appreciated that thematerials described herein can be combined in numerous ways to formdifferent mold materials for use in the present invention.

According to some embodiments, hardening or curing of a composition orother material, solution, dispersion, or the like of the presentinvention includes hardening, such as for example by chemical reactionlike a polymerization, phase change, a melting/cooling transition,evaporation, moisture cure, combinations thereof, and the like.

In some embodiments of the present invention the mold and/or substratematerials are preferably flexible, non-toxic, substantially UVtransparent, highly gas permeable, highly fluorinated, has a high freevolume, tough, have a low surface energy, are highly permeable tooxygen, carbon dioxide, and nitrogen, are substantially resistant toswelling, combinations thereof, and the like. The properties of thesematerials can be tuned over a wide range through the judicious choice ofadditives, fillers, reactive co-monomers, and functionalization agents.

In other embodiments, the mold or substrate used in the presentinvention can includes a material selected from the group including afluoropolymer, a perfluoropolyether, a fluoroolefin, an acrylate, asilicone such as for example polydimethylsiloxane (PDMS) or fluorinatedPDMS, a styrenic, a fluorinated thermoplastic elastomer (TPE), atriazine fluoropolymer, a perfluorocyclobutyl, a fluorinated epoxy, afluorinated monomer or fluorinated oligomer that can be polymerized orcrosslinked, a combination thereof, or the like.

Further, in some embodiments, the materials used herein are selectedfrom highly fluorinated fluoroelastomers, e.g., fluoroelastomers havingat least fifty-eight weight percent fluorine, as described in U.S. Pat.No. 6,512,063 to Tang, which is incorporated herein by reference in itsentirety. Such fluoroelastomers can be partially fluorinated orperfluorinated and can contain between 25 to 70 weight percent, based onthe weight of the fluoroelastomer, of copolymerized units of a firstmonomer, for example but not limitation, vinylidene fluoride (VF₂) ortetrafluoroethylene (TFE). The remaining units of the fluoroelastomerscan include one or more additional copolymerized monomers and can beselected from the group of fluorine-containing olefins, fluorinecontaining vinyl ethers, hydrocarbon olefins, combinations thereof, andthe like.

Fluoroelastomers that can be used in the presently disclosed subjectmatter include, but are not limited to, those having at least 58 wt. %fluorine and having copolymerized units of i) vinylidene fluoride andhexafluoropropylene; ii) vinylidene fluoride, hexafluoropropylene andtetrafluoroethylene; iii) vinylidene fluoride, hexafluoropropylene,tetrafluoroethylene and 4-bromo-3,3,4,4-tetrafluorobutene-1; iv)vinylidene fluoride, hexafluoropropylene, tetrafluoroethylene and4-iodo-3,3,4,4-tetrafluorobutene-1; v) vinylidene fluoride,perfluoro(methyl vinyl)ether, tetrafluoroethylene and4-bromo-3,3,4,4-tetrafluorobutene-1; vi) vinylidene fluoride,perfluoro(methyl vinyl)ether, tetrafluoroethylene and4-iodo-3,3,4,4-tetrafluorobutene-1; vii) vinylidene fluoride,perfluoro(methyl vinyl)ether, tetrafluoroethylene and1,1,3,3,3-pentafluoropropene; viii) tetrafluoroethylene,perfluoro(methyl vinyl)ether and ethylene; ix) tetrafluoroethylene,perfluoro(methyl vinyl)ether, ethylene and4-bromo-3,3,4,4-tetrafluorobutene-1; x) tetrafluoroethylene,perfluoro(methyl vinyl)ether, ethylene and4-iodo-3,3,4,4-tetrafluorobutene-1; xi) tetrafluoroethylene, propyleneand vinylidene fluoride; xii) tetrafluoroethylene and perfluoro(methylvinyl)ether; xiii) tetrafluoroethylene, perfluoro(methyl vinyl)ether andperfluoro(8-cyano-5-methyl-3,6-dioxa-1-octene); xiv)tetrafluoroethylene, perfluoro(methyl vinyl)ether and4-bromo-3,3,4,4-tetrafluorobutene-1; xv) tetrafluoroethylene,perfluoro(methyl vinyl)ether and 4-iodo-3,3,4,4-tetrafluorobutene-1; andxvi) tetrafluoroethylene, perfluoro(methyl vinyl)ether andperfluoro(2-phenoxypropyl vinyl)ether.

Further, the presently described fluoroelastomers can, in someembodiments, include units of one or more cure site monomers. Examplesof suitable cure site monomers include: i) bromine-containing olefins;ii) iodine-containing olefins; iii) bromine-containing vinyl ethers; iv)iodine-containing vinyl ethers; v) fluorine-containing olefins having anitrile group; vi) fluorine-containing vinyl ethers having a nitrilegroup; vii) 1,1,3,3,3-pentafluoropropene (2-HPFP), viii)perfluoro(2-phenoxypropyl vinyl)ether; and ix) non-conjugated dienes.Units of cure site monomer, when present in the presently disclosedfluoroelastomers, are typically present at a level of 0.05-110 wt. %(based on the total weight of fluoroelastomer), preferably 0.05-5 wt. %and most preferably between 0.05 and 3 wt. %.

In some embodiments the fluoropolymer or perfluoropolyether mold and/orsubstrate material is endcapped with an epoxy moiety that can bephotocured using a photoacid generator. According to some embodiments,the materials for the mold and/or substrate can include end groups, suchas for example: methacrylates; acrylates; styrenics; epoxides;cyclobutanes and other 2+2 cycloadditions; aryl trifluorovinyl ether(TVE); fluoroalkyliodide; cycloaliphatic epoxides; poly(ethyleneglycol); diisocyanate; three-armed triol; distyrene; imidazoles;diamine; tetrol; triol; diepoxy; diisocyanate; diurethanedimethacrylate, combinations thereof; and the like.

Further embodiments of molds of the present invention are disclosed inthe following references, which are hereby incorporated in theirentirety: WO 2007/021762 filed Aug. 9, 2006; WO 2005/084191 filed Feb.14, 2005; and U.S. 2007-0275193 filed Aug. 11, 2006.

Particles and Films

According to some embodiments, particles and/or patterned films may beformed in cavities 54 of mold 38. In some embodiments, substantiallyliquid composition 40 may be applied to mold 38, as described herein, toform particles and/or a patterned film. In some embodiments,substantially liquid composition 40 includes a liquid precursor.

In some embodiments, a particle has a size and shape that substantiallymimics the size and shape of the cavity of mold 38 in which the particlewas formed. In some embodiments, a particle has a substantiallypredetermined size and shape.

Particles and patterned films of some embodiments of the presentinvention are, in some embodiments, molded in low surface energy molds,methods, and materials described in the following patent applications:International Patent Application Serial No. PCT/US06/034997, filed Sep.7, 2006 and published as WO 07/030698; International Patent ApplicationSerial No. PCT/US06/043305 filed Nov. 7, 2006 and published as WO07/094,829, each of which is incorporated herein by reference in itsentirety including all references cited therein.

In some embodiments, each particle of a plurality of particles isconfigured with a substantially predetermined size and shape. In someembodiments, the manufacturing process may produce particles withinherent variations in shape. In some embodiments, the shape of theparticles may vary from the shape of mold 38. In some embodiments, theshape of the particles may vary from the shape of other particles in theplurality of particles. In certain embodiments, the variations of theshape of the particles may be nanoscale variations. In otherembodiments, the particles may have substantially identical shapes. Incertain embodiments, the particles may have identical shapes.

In some embodiments the material to be molded within cavities 54 of mold38 in the present invention include biologically active cargo, anelement, a molecule, a chemical substance, an agent, a therapeuticagent, a diagnostic agent, a pharmaceutical agent, a drug, a medication,genetic material, a nucleotide sequence, an amino-acid sequence, aligand, an oligopeptide, a protein, a vaccine, a biologic, DNA, RNA, acancer treatment, a viral treatment, a bacterial treatment, a fungaltreatment, an auto-immune treatment, a psychotherapeutic agent, animaging agent, a contrast agent, an antisense agent, radiotracers and/orradiopharmaceuticals combinations thereof, and the like. In someembodiments the oligonucleotide includes, but is not limited to an RNA,siRNA, dsRNA, ssRNA, miRNA, rRNA, tRNA, snRNA, sliRNA, DNA, ssDNA,dsDNA, plasmid DNA, or vaccine.

In some embodiments, the material to be molded within cavities 54 ofmold 38 include, without limitation, one or more of a polymer, a liquidpolymer, a solution, a monomer, a plurality of monomers, a chargedmonomer, a water soluble monomer, a polymerization initiator, apolymerization catalyst, an inorganic precursor, an organic material, anatural product, a metal precursor, a pharmaceutical agent, a tag amagnetic material, a paramagnetic material, a ligand, a cell penetratingpeptide, a porogen, a surfactant, a plurality of immiscible liquids, asolvent, a charged species, combinations thereof, or the like. In someembodiment, the material to be molded in cavities 54 of mold 38 include,but are not limited to, photovoltaic materials, optical materials,transparent materials, translucent materials, opaque materials,conductive materials, combinations thereof, and the like.

In some embodiments, the monomer includes butadienes, styrenes, propene,acrylates, methacrylates, vinyl ketones, vinyl esters, vinyl acetates,vinyl chlorides, vinyl fluorides, vinyl ethers, vinyl pyrrolidone,acrylonitrile, methacrylnitrile, acrylamide, methacryl amide allylacetates, fumarates, maleates, ethylenes, propylenes,tetrafluoroethylene, ethers, isobutylene, fumaronitrile, vinyl alcohols,acrylic acids, amides, carbohydrates, esters, urethanes, siloxanes,formaldehyde, phenol, urea, melamine, isoprene, isocyanates, epoxides,bisphenol A, alcohols, chlorosilanes, dihalides, dienes, alkyl olefins,ketones, aldehydes, vinylidene chloride, anhydrides, saccharide,acetylenes, naphthalenes, pyridines, lactams, lactones, acetals,thiiranes, episulfide, peptides, derivatives thereof, and combinationsthereof.

In yet other embodiments, the polymer includes polyamides, proteins,polyesters, polystyrene, polyethers, polyketones, polysulfones,polyurethanes, polysiloxanes, polysilanes, cellulose, amylose,polyacetals, polyethylene, glycols, poly(acrylate)s,poly(methacrylate)s, poly(vinyl alcohol), poly(vinylidene chloride),poly(vinyl pyrrolidone), poly(vinyl acetate), poly(ethylene glycol),polystyrene, polyisoprene, polyisobutylenes, poly(vinyl chloride),poly(propylene), poly(lactic acid), polyisocyanates, polycarbonates,alkyds, phenolics, epoxy resins, polysulfides, polyimides, liquidcrystal polymers, heterocyclic polymers, polypeptides, conductingpolymers including polyacetylene, polyquinoline, polyaniline,polypyrrole, polythiophene, and poly(p-phenylene), dendimers,fluoropolymers, derivatives thereof, combinations thereof, and the like.

A co-constituent of the particle, such as a polymer for example, can becross-linked to varying degrees. Depending upon the amount ofcross-linking of the polymer, another co-constituent of the particle,such as a cargo, can be configured to be released from the particle asdesired. The cargo can be released with no restraint, controlledrelease, or can be completely restrained within the particle. In someembodiments, the particle can be functionalized, according to methodsand materials disclosed herein, to target a specific biological site,cell, tissue, agent, combinations thereof, or the like. Upon interactionwith the targeted biological stimulus, a co-constituent of the particlecan be broken down to begin releasing the active co-constituent of theparticle. In one example, the polymer can be poly(ethylene glycol)(PEG), which can be cross-linked between about 5% and about 100%. In oneembodiment, when the PEG co-constituent is cross-linked about 100%, nocargo leaches out of the particle.

In some embodiments, the particle includes a biodegradable polymer. Inother embodiments, the polymer is modified to be a biodegradablepolymer, e.g., a poly(ethylene glycol) that is functionalized with adisulfide group. In other embodiments, the polymer is modified to be abiodegradable polymer, e.g., a polyacrylic acid ester that isfunctionalized with a disulfide group. In some embodiments, thebiodegradable polymer includes, without limitation, one or more of apolyester, a polyanhydride, a polyamide, a phosphorous-based polymer, apoly(cyanoacrylate), a polyurethane, a polyorthoester, apolydihydropyran, a polyacetal, combinations thereof, or the like.Further polymers that can be used in particles of the present inventionare disclosed in Biodegradable Hydrogels for Drug Delivery, Park K.,Shalaby W., Park H., CRC Press, 1993, which is incorporated herein byreference in its entirety.

In some embodiments, the polyester includes, without limitation, one ormore of polylactic acid, polyglycolic acid, poly(hydroxybutyrate),poly(ε-caprolactone), poly(β-malic acid), poly(dioxanones), combinationsthereof, or the like. In some embodiments, the polyanhydride includes,without limitation, one or more of poly(sebacic acid), poly(adipicacid), poly(terpthalic acid), combinations thereof, or the like. In yetother embodiments, the polyamide includes, without limitation, one ormore of poly(imino carbonates), polyaminoacids, combinations thereof, orthe like.

In some embodiments, a cargo such as a biologically active cargo can becombined with the particle material. In some embodiments, the cargo is apharmaceutical agent. The pharmaceutical agent can be, but is notlimited to, a drug, a peptide, RNA, RNAi, siRNA, shRNA, DNA,combinations thereof, or the like.

In some embodiments, the matrix composition of the particles isconfigured to biodegrade in the presence of an intercellular orintracellular stimulus. In some embodiments, the particles areconfigured to degrade in a reducing environment. In some embodiments,the particles contain crosslinking agents that are configured to degradein the presence of an external stimulus. In some embodiments, thecrosslinking agents are configured to degrade in the presence of a pHcondition, a radiation condition, an ionic strength condition, anoxidation condition, a reduction condition, a temperature condition, analternating magnetic field condition, an alternating electric fieldcondition, combinations thereof, or the like. In some embodiments, theparticles contain crosslinking agents that are configured to degrade inthe presence of an external stimulus, a targeting ligand, and atherapeutic agent. In some embodiments, the therapeutic agent is a drugor a biologic. In some embodiments the therapeutic agent is DNA, RNA,shRNA, or siRNA.

A further approach is to synthesize a polymer that contains an unstablecrosslinker. In some embodiment, this crosslinker can degrade basedthrough hydrolysis, enzymatic cleavage, changes in temperature, pH, orother environments such as oxidation or reduction. Crosslinking groupscan include hydrolytically labile carbonate, ester, and phosphazenelinkers, lactide or glycolide, and alpha hydroxy acids such as glycolic,succinic, or lactic acid. Cross-linkers of the present invention mayalso include a degradable region containing one or more groups such asanhydride, an orthoester, and/or a phosphoester. In certain cases thebiodegradable region may contain at least one amide functionality. Thecross-linker of the present invention may also include an ethyleneglycol oligomer, oligo(ethylene glycol), poly(ethylene oxide),poly(vinyl pyrolidone), poly(propylene oxide), poly(ethyloxazoline), orcombinations of these substances.

In some embodiments, crosslinkers of the present invention includereduction/oxidation cleavable crosslinkers, such as a disulfide bridges,azo linkages, combinations thereof, or the like. Crosslinkerssusceptible to pH changes are also included; these systems can be stableunder acidic or basic conditions and start to degrade at blood pH or canbe base- or acid-catalyzed.

Hydrolytically degradable crosslinking agents that may be used forforming degradable organic particles include, but are not limited to,poly(ε-caprolactone)-b-tetraethyleneglycol-b-poly(ε-caprolactone)dimethacrylate,poly(ε-caprolactone)-b-poly(ethyleneglycol)-b-poly(ε-caprolactone)dimethacrylate, poly(lacticacid)-b-tetraethylene glycol-b-poly(lactic acid)dimethacrylate,poly(lactic acid)-b-poly(ethylene glycol)-b-poly(lacticacid)dimethacrylate, poly(glycolic acid)-b-tetraethyleneglycol-b-poly(glycolic acid)dimethacrylate, poly(glycolicacid)-b-poly(ethylene glycol)-b-poly(glycolic acid)dimethacrylate,poly(ε-caprolactone)-b-tetraethyleneglycol-b-poly(ε-caprolactone)diacrylate,poly(ε-caprolactone)-b-poly(ethyleneglycol)-b-poly(ε-caprolactone)diacrylate, poly(lacticacid)-b-tetraethylene glycol-b-poly(lactic acid)diacrylate, poly(lacticacid)-b-poly(ethylene glycol)-b-poly(lactic acid) diacrylate,poly(glycolic acid)-b-tetraethylene glycol-b-poly(glycolicacid)diacrylate, poly(glycolic acid)-b-poly(ethyleneglycol)-b-poly(glycolic acid)diacrylate, and mixtures thereof. Furthercrosslinkers that can be used in particles of the present invention aredisclosed in Biodegradable Hydrogels for Drug Delivery, Park K., ShalabyW., Park H., CRC Press, 1993, which is incorporated herein by referencein its entirety.

Enzymatically degradable crosslinking agents that may be used forforming degradable organic particle include, but are not limited to,crosslinking agents in which a short sequence of amino acids (forexample, 3-5 amino acids) are linked to two methacrylate or acrylategroups. Examples of enzymatically degradable crosslinking agentsinclude, but are not limited to,alanine-proline-glycine-leucine-poly(ethyleneglycol)-alanine-proline-glycine-leucine)-diacrylate,alanine-proline-glycine-leucine-diacrylate,alanine-proline-glycine-leucine-poly(ethyleneglycol)-alanine-proline-glycine-leucine)-dimethylacrylate-, andalanine-proline-glycine-leucine-dimethylacrylate, combinations thereof,and the like. Other enzymatically degradable crosslinking agents aredisclosed in West & Hubbell (1999) Macromolecules 32(1):241-4, which isincorporated herein by reference in its entirety. Other enzymaticallycleaved crosslinkers contain azobonds. In some embodiments ahydrolytically labile crosslinker can be fabricated for use in theparticles and structured surfaces of the present invention. An exampleof a hydrolytically labile crosslinker includespoly(ε-caprolactone)-b-tetraethyleneglycol-b-poly(ε-caprolactone)dimethacrylate.

In some embodiments, the particle includes a therapeutic or diagnosticagent coupled with the particle. The therapeutic or diagnostic agent canbe physically coupled or chemically coupled with the particle,encompassed within the particle, at least partially encompassed withinthe particle, coupled to the exterior of the particle, entangled withinthe matrix of the particle, crosslinked into the particle, covalentlybonded to the matrix of the particle, held in the particle byhydrophobic/hydrophilic forces, combinations thereof, and the like. Thetherapeutic agent can be a drug, a biologic, a ligand, an oligopeptide,a cancer treating agent, a viral treating agent, a bacterial treatingagent, a fungal treating agent, combinations thereof, or the like.

According to other embodiments, one or more other drugs can be includedwith the particles and structured surfaces of the presently disclosedsubject matter and can be found in Physicians' Desk Reference, ThomsonHealthcare, 61^(st) ed. (2007), which is incorporated herein byreference in its entirety.

Films

According to some embodiments, a system of the present inventionincludes substrate 42, as shown in FIG. 4. In some embodiments,substrate 42 may include the materials described herein for mold 38 ofthe present invention. In some embodiments, substrate 42 is flexible. Inother embodiments, substrate 42 is rigid. In some embodiments, substrate42 may include at least one of a wafer, glass, plastic, polycarbonate,PEN, or PET. In some embodiments, substrate 42 is sacrificial. In someembodiment the substrate of the present invention includes substratesthat have a selected affinity or lack of affinity for materials to bemolded within the cavities of the present invention. In someembodiments, the substrate includes a surface energy below about 25mN/m.

Further embodiments of substrates and molds of the present invention aredisclosed in the following references, which are hereby incorporated intheir entirety: WO 2007/021762 filed Aug. 9, 2006; WO 2005/084191 filedFeb. 14, 2005; and U.S. 2007-0275193 filed Aug. 11, 2006.

Method of Forming Particles

In some embodiments, a system of the present invention is used to formparticles of a substantially predetermined size and shape as describedherein.

In some embodiments, a method of forming particles includes applyingsubstantially liquid composition 40, as described herein, to mold 38. Asdescribed herein, mold 38 of the present invention may define aplurality of cavities. In some embodiments, substantially liquidcomposition 40 may be applied to mold 38 before mold 38 reaches a nippoint. In certain embodiments, substantially liquid composition 40 maybe applied between mold 38 and substrate 42.

In some embodiments, mold 38 is nipped between roller 10 and surface 11.In some embodiments mold 38 is nipped at the nip point 14, 18. Accordingto certain embodiments, mold 38 may be nipped between roller 10 andsurface 11 such that substantially liquid composition 40 enters cavities54 of mold 38. The some embodiments, nipping mold 38 between roller 10and surface 11 includes urging surface 11 towards roller 10. In otherembodiments, nipping mold 38 between roller 10 and surface 11 includesurging roller 10 towards surface 11. A predetermined amount of pressuremay be applied to mold 38 at nip point 14, 18.

In some embodiments, substrate 42 and mold 38 are nipped by roller 10and surface 11. In some embodiments, surface 11 is the surface of secondroller 12. In some embodiments, surface 11 is the surface of plate 16.

A variety of system parameters may be selected for a desiredapplication. Significant to this art, pressures are utilized to bringcomponents into predetermined proximities and contact times and the flowcontrol of the liquid compositions is principally achieved by capillaryforce and material surface properties not hydraulic pressures.Parameters may be selected based on the desired contact area of mold 38and/or substrate 42 at the nip point, the desired contact time at thenip point, thickness of mold 38, the flexibility of the components inthe system, the desired speed at which the system is to be run, theangles of the substrate and mold upon entering the nip point,combinations thereof, and the like. Referring to FIGS. 9A-9C, the rollermaterials and the pressure, which may be controlled by the position ofrollers 10, 12, at nip point 14, 18 may have an impact on the conditionsat nip point 14, 18 for forming and controlling proximities between themolds and cover films. As shown in FIG. 9A, soft roller 10 and/or a highpressure at nip point 14 may result in a larger contact area through nippoint 14. In contrast, FIG. 9B shows that harder roller 10 and/or alower pressure at nip point 14 may result in a smaller contact areathrough nip point 14. The variation in contact areas based on rollerhardness and/or pressure, which may be adjusted by the position ofrollers 10, 12, may impact the amount of time and the pressure at whichmold 38 and substrate are nipped between rollers 10, 12. As shown inFIG. 9C, nip point 18 formed by roller 10 and the surface of plate 16may result in a flat interface rather than a curved interface shown inFIGS. 9A and 9B. Nip point 18 may be formed with any roller hardness,and may be suitable for nipping fragile substrates such as wafers orglass. In some embodiments, the footprint between the softer roller anda harder surface generates zones of alternative speeds from deformationof the softer roller. The deformation of the footprint can be adjustedbased on pressures, roller hardness, and the like to generate a desiredfootprint for a particular application.

According to some embodiments, substantially liquid composition 40 maybe hardened in cavities 54 of mold 38 to form a particle in each cavity.In some embodiments, the particles are hardened by curing. The curingmay be passive or active curing. In certain embodiments, the particlesmay be hardened by heat, radiation, pressure, moisture, combinationsthereof, or the like. According to certain embodiments, heat is suppliedthrough rollers 10, 12 or plates.

In certain embodiments, the particle has a size and shape thatsubstantially mimics the size and shape of mold 38. In some embodiments,the particle is harvested from mold 38.

Referring to FIG. 10, in some embodiments mold 38 and substrate 42 maybe nipped between the surface of plate 16 and roller 10. In someembodiments, substrate 42 and mold 38 are nipped between roller 10 andplate 16 to laminate substrate 42 to mold 38. According to someembodiments, mold 38 may approach nip point 18 at predetermined angle 44relative to the surface of plate 16. In certain embodiments, substrate42 may approach nip point 18 horizontally along plate 16. Beforenipping, substantially liquid composition 40 may be applied to mold 38and/or substrate 42. Substantially liquid composition 40 may be appliedbetween roller 10 and substrate 42. In some embodiments, entry of thesubstantially liquid composition 40 into mold 38 cavities is acceleratedand/or urged by roller 10 and the surface of plate 16. In someembodiments, a predetermined amount of pressure is applied at nip point18 to accelerate and/or urge substantially liquid composition 40 intomold 38 cavities. In some embodiments, substrate 42 is laminated to mold38 with mold 38 cavities containing substantially liquid composition 40.In some embodiments, composition 40 in mold 38 cavities is trapped bysubstrate 42. According to certain embodiments, the system of FIG. 10 issuitable for volatile substantially liquid compositions 40. In someembodiments, substantially liquid composition 40 is hardened in cavities54 of mold 38. According to some embodiments, after substantially liquidcomposition 40 is hardened in mold 38 cavities, the particles may beharvested by stripping mold 38 from substrate 42. In other embodiments,the particles may be harvested by stripping substrate 42 from mold 38.

Referring to FIG. 11, in some embodiments mold 38 and substrate 42 maybe nipped between the surface of plate 16 and roller 10. In someembodiments, substrate 42 may approach nip point 18 at predeterminedangle 44. Substrate 42 may include, for example, PET. Substrate 42 mayinclude other high surface energy materials. According to certainembodiments, mold 38 may approach nip point 18 horizontally along plate16. Before nipping, substantially liquid composition 40 may be appliedto mold 38 and/or substrate 42. Substantially liquid composition 40 maybe applied between mold 38 and substrate 42. In some embodiments, entryof substantially liquid composition 40 into mold 38 cavities isaccelerated by roller 10 and the surface of plate 16. In someembodiments, a predetermined amount of pressure is applied at nip point18 to accelerate entry and/or urge substantially liquid composition 40into mold 38 cavities. Once substantially liquid composition 40 entersmold 38 cavities, composition 40 may be hardened to form particles.According to some embodiments, substrate 42 moves away from nip point 18at predetermined angle 46 relative to the surface of plate 16. Mold 38may move away from nip point 18 horizontally along the surface of plate16. In certain embodiments, substrate 42 is separated from mold 38 assubstrate 42 and mold 38 move away from nip point 18. In someembodiments, the particles adhere to substrate 42. In certainembodiments, the particles adhere to substrate 42 and are removed frommold 38 cavities when substrate 42 is separated from mold 38. Accordingto some embodiments, the adherence of the particles to substrate 42 isrelated to angle 46 relative to the surface of plate 16 at whichsubstrate 42 moves away from nip point 18.

Referring to FIG. 12, in some embodiments a system includes multiple nippoints, such as first nip point 14 and second nip point 18. In someembodiments, substantially liquid composition 40 is applied to mold 38.Composition 40 may be applied to mold 38 prior to mold 38 reaching firstnip point 14. In some embodiments, first nip point 14 may be formed byroller 10 and the surface of second roller 12. Rollers 10, 12 may bepositioned to form desired nip point 14. In some embodiments, secondroller 12 is coated in a substance to which substantially liquidcomposition 40 does not adhere. In some embodiments, second roller 12 iscovered in a layer of PE or PTFE. Rollers 10, 12 may turn at apredetermined rate to push mold 38 through nip point 14. Composition 40may be accelerated into mold 38 cavities by roller 10 and second roller12 at first nip point 14. In some embodiments, a predetermined amount ofpressure is applied at nip point 14 to accelerate substantially liquidcomposition 40 into mold 38 cavities. In some embodiments, mold 38 isnipped by roller 10 and a second surface at second nip point 18. Incertain embodiments, the second surface is the surface of plate 16.Roller 10 and plate 16 may be positioned to form desired nip point 18.In certain embodiments, mold 38 and substrate 42 are nipped betweenroller 10 and the surface of plate 16 at second nip point 18. In someembodiments, mold 38 approaches second nip point 18 at predeterminedangle 44 relative to the surface of plate 16. According to someembodiments, mold 38 cavities contain substantially liquid composition40 prior to reaching second nip point 18. Substrate 42 may approachsecond nip point 18 horizontally along the surface of plate 16. In someembodiments, substrate 42 is laminated to mold 38 at second nip point18. In some embodiments, a predetermined amount of pressure is appliedto mold 38 and substrate 42 at second nip point 18 to laminate substrate42 to mold 38. The liquid composition may be hardened in mold 38cavities to form particles. In some embodiments, the particles may becaptured in mold 38 cavities by substrate 42. In some embodiments, sucha system is suitable for volatile liquids.

Method of Harvesting Particles

In some embodiments, systems and methods of the present inventionharvest particles. Referring to FIG. 13A, in some embodiments laminate52 is formed from base 56 which is treated with soluble substance 58. Incertain embodiments, base 56 may include polyethylene terephthalate(PET). According to some embodiments, soluble substance 58 includespolyvinyl pyrrolidone (PVP). Referring the FIG. 13B, in certainembodiments particle 60 as described herein is adhered to solublesubstance 58. Referring to FIG. 13C, in one embodiment particle 60,contained within cavity 54 of fluoropolymer mold 38, may be engaged withsoluble substance 58 to adhere particle 60 to soluble substance 58 onbase 56 and thereby remove particle 60 from cavity 54.

Referring to FIGS. 14 and 15, in certain embodiments a solvent isapplied to laminate 52 proximate nip point 14, 18. In some embodiments,solvent 48 is contained within a boundary of laminate 52. Solvent 48 maybe contained within the boundary of laminate 52 by applying air stream50 toward solvent 48.

In some embodiments, solvent 48 is selected to dissolve solublesubstance 58. In some embodiments, soluble substance 58 is selectedaccording to a composition of particle 60 and what will bind or have anaffinity for particle 60. In some embodiments, solvent 48 is water.Solvent 48 is capable of dissolving soluble substance 58. In someembodiments, solvent 48 dissolves soluble substance 58 and releasesparticle 60 from laminate 52 into a solution of soluble substance 58 andsolvent 48. In some embodiments, the particle 60 forms a dispersion in asolution of soluble substance 58 and solvent 48. In certain embodiments,the solution is collected.

Referring to FIG. 15, in some embodiments laminate 52 with base layer56, soluble substance 58, and adhered particle 60 is nipped betweenroller 10 and surface 11 of second roller 12. In some embodiments,roller 10 includes an elastic material, e.g., rubber. In someembodiments, second roller 12 includes an inelastic material, e.g.,stainless steel. In certain embodiments, roller 10 and second roller 12are positioned relative to each other to form desired nip point 14.Roller 10 and second roller 12 may turn against each other at a desiredspeed to move laminate 52 through nip point 14. According to certainembodiments, solvent 48 such as water is applied to laminate 52proximate nip point 14. Air jets 50 may be applied to solvent 48 tocontain solvent 48 within the boundary of laminate 52. Solvent 48 maydissolve soluble substance 58 on laminate 52 to release particle 60 fromlaminate 52 into absolution of soluble substance 58 and solvent 48. Insome embodiments, the particle 60 forms a dispersion of particles in asolution of soluble substance 58 and solvent 48. Base layer 56 mayproceed through and away from nip point 14.

In some embodiments, particles 60 are harvested from mold 38 by aharvesting nip. A harvesting nip may be configured and dimensioned toreceive mold 38 with filled cavities 54 and nip mold 38 against aharvesting layer or substrate 42 such that the composition in cavities54 of mold 38 is released from cavity 54 and remains on the harvestinglayer or substrate 42. In some embodiments, the substance released fromcavity 54 into a solution is then collected.

Referring again to FIG. 8, particles 60 may be harvested by nipping mold38 and substrate 42 to release particles 60 onto substrate 42. In someembodiments, substrate 42 and mold 38 are nipped by roller 34 and plate16. In certain embodiments, the mold cavities 54 contain particles 60.Roller 10 and plate 16 may move to guide mold 38 and substrate 42 topass through nip point 32 at a desired speed. In some embodiments, mold38 is separated from substrate 42 after passing through nip point 32. Incertain embodiments, mold 38 moves away from nip point 32 at apredetermined angle relative to the surface of plate 16. In someembodiments, 42 substrate moves away from nip point 32 horizontallyalong the surface of plate 16. According to certain embodiments,particles 60 may be released from mold 38 on substrate 42 after nippoint 32 as mold 38 is separated from substrate 42. In some embodiments,the release of particles 60 onto substrate 42 is dependent on thepredetermined angle at which mold 38 moves away from nip point 32.

Method of Forming Patterned Films

In some embodiments, patterned films can be fabricated with the systemof the present invention. Patterned films can be made by applyingsubstantially liquid composition 40 to mold 38 and laminatingsubstantially liquid composition 40 between mold 38 and a film in a niproller. Nipping this laminate accelerates entry of substantially liquidcomposition 40 into cavities 54 of mold 38 while excess composition 40remains between the film and mold 38. In some embodiments the combinedmold 38, composition 40, and film is treated to harden or curesubstantially liquid composition 40 into a patterned film. Accordingly,after hardening, mold 38 is separated from the film and the patternedfilm, and the patterned film includes the hardened composition that bothentered cavities 54 of mold 38 and the excess that remained between thefilm and mold 38. The portion of the hardened composition that enteredcavities 54 of the mold 38 results in structures having substantiallythe same shape and size of cavities 54. In some embodiments, thepressures of rollers 10, 12, distances between rollers 10, 12 and/orsurfaces 11, quantity of materials, temperatures, speeds, time, andother parameters of the present invention can be adjusted to result in adesired thickness of patterned film, materials of the patterned films,or the like.

In other embodiments, after the film is laminated to mold 38 withcomposition 40 therebetween, the film can be removed to yield moldcavities 54 filled with composition and virtually no or no compositionon the surface of mold 38 between cavities 54. Next, a second film islaminated onto mold 38. After laminating the second film onto mold 38,the combination is treated to harden or cure composition 40 into solidstructures on a surface of the patterned film.

In a preferred embodiment the materials used to fabricate the patternedfilms include optical materials, such as optical polymers, conductingpolymers, organic optoelectronic materials, and the like. The opticalpolymers include properties such as, but not limited to, high opticalclarity, resistance to yellowing, extremely low outgassing, wide rangeof refractive index, resistance to high radiation flux, very low to veryhigh temperature service ranges, low trace ionics for sensitiveelectro-optics, the ability to withstand high strain withoutdelamination, combinations thereof, and the like.

The present invention is not to be limited in scope by the specificembodiments disclosed herein which are intended as illustrations of afew aspects of the invention and any embodiments which are functionallyequivalent are within the scope of this invention. Indeed, variousmodifications of the invention in addition to those shown and describedherein will become apparent to those skilled in the art and are intendedto fall within the appended claims.

Each reference identified herein is hereby incorporated by reference asif set forth in its entirety.

1. A method of forming nanoparticles, comprising (a) applying asubstantially liquid composition to a mold, wherein the mold comprises apolymer and defines a plurality of cavities each having a broadestcross-sectional dimension of less than about 100 micrometers; (b)passing the mold through a nip point such that the substantially liquidcomposition enters the cavities of the mold, wherein passing the moldthrough the nip point comprises nipping the substantially liquidcomposition between a cover sheet and the mold; (c) removing the coversheet from the mold such that the substantially liquid composition notin the cavities of the mold remains adhered to the cover sheet, the landarea of the mold between the cavities is substantially free from thesubstantially liquid composition, and the cavities of the mold remainfilled with the substantially liquid composition; and (d) hardening thesubstantially liquid composition in the cavities of the mold to form aparticle within each cavity, wherein the particle has a size and shapethat substantially mimics the size and shape of the cavity of the mold.2. The method of claim 1, further comprising, after hardening,harvesting the particles from the mold.
 3. The method of claim 1,further comprising, before hardening, nipping the mold with a substrateto laminate the substrate to the mold.
 4. The method of claim 3, furthercomprising after nipping the mold with the substrate, hardening thesubstantially liquid composition and harvesting the particle from themold, wherein the harvesting includes separating the substrate from themold such that the substrate moves away from the mold with the particlesdisposed on the substrate.
 5. The method of claim 4, wherein thesubstrate is removed from the mold at a predetermined angle.
 6. Themethod of claim 1, wherein the polymer mold comprises a fluoropolymer.7. The method of claim 1, wherein the polymer mold comprises afluoropolyether.
 8. The method of claim 1, further comprising, afterremoving the cover sheet, contacting the mold with a harvest sheet. 9.The method of claim 8, wherein the harvest sheet comprises an affinityfor the particles in the cavities of the mold.
 10. The method of claim8, wherein the harvest sheet comprises a soluble substance having anaffinity for the particles in the cavities of the mold.
 11. The methodof claim 10, further comprising removing the harvest sheet from the moldsuch that the particles are released from the cavities of the mold andremain in contact with the soluble substance of the harvest sheet. 12.The method of claim 11, further comprising releasing the particles fromthe harvest sheet by treating the harvest sheet with a solvent selectedto dissolve the soluble substance.
 13. The method of claim 12, furthercomprising forming a dispersion with the particles in a solution of thesolvent and the soluble substance.
 14. The method of claim 1, whereinthe cover sheet comprises a closed loop.
 15. The method of claim 1,wherein the cover sheet is disposed about a roller.
 16. The method ofclaim 1, wherein each of the cavities of the plurality of cavities has alargest dimension of less than about 10 micrometers.
 17. The method ofclaim 1, wherein each of the cavities of the plurality of cavities has alargest dimension of less than about 1 micrometer.